ABSTRACT Each year nearly 800,000 people suffer a new or recurrent stroke in the United States. Approximately 85% of these patients survive and require rehabilitation making it the leading cause of long-term disability in the U.S. Approximately 4 million Americans are living with the effects of stroke and millions of family/friends are caregivers. The estimated direct and indirect costs of stroke continue to escalate (e.g. in 2003 was $57 billion, 2008 was $65.5 billion, and for 2010 is estimated to be $73.7 billion). The mean lifetime cost of ischemic stroke in the US is estimated at $140,048, including inpatient care, rehab, and follow-up care. The majority of stroke costs are towards long-term care and rehabilitation (> $100,000/patient). Stroke rehabilitation in the latter stages of stroke is limited because most health care insurance pays only for limited rehabilitation visits (12-24 outpatient rehabilitation visits). Yet there is room for improvement in terms of decreasing morbidity and improving functional independence in these stroke patients, given that 1/3 of patients have some type of residual deficits. Although there are already several rehabilitation techniques aimed at stroke recovery including traditional physical-occupational-speech therapy, novel therapies such as constraint-induced movement therapy, robot- aided therapy, Transcranial Magnetic Stimulation (TMS), virtual reality (VR), a number of these suffer from issues of passive movement repetition, large equipment, personnel/time constraints, and high costs. Furthermore few harness brain plasticity to derive therapeutic interventions. The recommendations from the 2009 workshop sponsored by the NIH blueprint for neuroscience research heralded the translation of neuroplasticity as key to developing guidelines for effective clinical therapies in rehabilitation. Aim 1: To investigate the efficacy of BCI-FES vs. standard FES(current standard of care), as measured by changes in behavioral measures in stroke patients. A more recent development has been the use of a more active rehabilitation approach that harnesses brain plasticity in which brain thoughts inferred by EEG-based Brain Computer Interface (BCI)system are linked to functional electrical stimulation (FES) of the muscles to replace or assist function that is lost in neurologically impaired individuals. In recent animal and human studies, active stimulation by coordinating central brain activation with peripheral movement has been shown to elicit greater functional recovery than passive stimulation or peripheral movements. This is presumably through the faster formation of latent plastic neural circuits between central and periphery which an active approach would foster. This proposal investigates this novel BCI technology that adopts an active intervention approach, non-invasive and aims to facilitate recovery after brain injury by restoring brain function while improving corresponding motor function. Aims 2 & 3: To track brain reorganization changes and behavioral changes induced by BCI-FES vs. standard FES (current standard of care) in stroke patients. We also propose to study the mechanisms underlying functional recovery using this approach by collecting fMRI, EEG and DTI at different time points so as to monitor the extent of brain changes and to delineate the areas and tracts that are associated with improvement in behavior. Recent studies of stroke rehabilitation have suggested that ipsilesional and contralesional areas and tracts play an important role in the recovery process. These areas and tracts may be adaptive and essential for recovery whereas others may be maladaptive. Future studies using the novel stroke rehabilitation device can be aimed at facilitating adaptive areas/tracts and suppressing maladaptive areas/tracts in order to optimize recovery.